Cryptococcus neoformans is the leading cause of fungal meningitis, a life-threatening infection that is often difficult to treat due to the poor arsenal of antifungal drugs. Cryptococcus neoformans is a fungal pathogen that causes meningoencephalitis primarily in AIDS patients and results in over 1 million active cases of cryptococcosis and 700,000 deaths per year worldwide. See, e.g., World Health Organization. (2003) HIV/AIDS Epidemiological surveillance update for the W.H.O. African region. World Health Organization, Geneva, Switzerland; Mitchell, et al., (1995) Clin. Microbiol. Rev. 8:515-548; Sorvillo, et al., (1997) AIDS 11, 673-679; Bicanic, et al., (2004) British Med. Bulletin, 72, 99-118; Zuger, et al., (1986) Ann Intern Med 104:234-240; Casadevall and Perfect (1998) Cryptococcus neoformans. American Society for Microbiology, Washington, D.C.; and Ecevit, et al., (2006) Clin Infect Dis 42:1443-1447. The global burden of cryptococcal meningitis remains a serious health concern as studies from Africa, India, Thailand and Asia-Pacific have all reported increases in the incidence of cryptococcal meningitis as an AIDS-defining illness and a leading cause of AIDS mortality. See, e.g., Park, B. J. et al., (2009). AIDS 23:525-530. In sub-Saharan Africa C. neoformans causes higher mortality than tuberculosis in the AIDS population. See, e.g., Park, B. J. et al., (2009) AIDS 23:525-530 Several outbreaks of cryptococcal infections (by the sibling species, C. gattii) in the Pacific Northwest of the US and Canada over the last 7 years have claimed the lives of 25% of the individuals infected, most of whom were not immunocompromised. See, e.g., Kidd, S. E. et al., (2004) PNAS 101:17258-17263. The most recent outbreak has occurred in Oregon and new outbreaks are expected in Northern California. See, e.g., Byrnes III, E. J., et al., (2010). Plos Pathogens 6:1-16.
Unfortunately, most patients present with significant fungal burden in the brain and consequently, death from cryptococcal infection results from brain edema and raised intracranial pressure. See, e.g., Zuger, A., et al., (1986) Ann Intern Med 104, 234-240. It remains a life-threatening infection in part because of the poor arsenal of antifungal agents available especially in parts of Africa where the most common drug available to combat this infection is merely a fungistatic drug (fluconazole). See, e.g., Warkentien, T., et al., (2010) Int J STD AIDS 10:679-684; Nussbaum, J. C., (2010) Clin Infect Dis 50:338-344. In these cases AIDS patients often require life-long maintenance therapy since in an immunosuppressed setting fungistatic drugs cannot clear cryptococcal infections. The batch of drugs currently available for the treatment of life-threatening fungal infections, like cryptococcal meningitis, is nowhere near what it should be. See, e.g., Warkentien, T., et al., (2010) Int J STD AIDS 10:679-684. Treatment for infected patients in North America usually involves amphotericin B in combination with flucytosine, however amphotericin B is quite toxic often resulting in renal damage and/or renal failure especially in older patients.
Virtually nothing is known about the role of secreted metalloproteases in the virulence and pathogenesis of C. neoformans. Remarkably it is still not clear why C. neoformans has this particular tropism for the CNS (central nervous system), nor have all the key cryptococcal proteins and signaling pathways facilitating its movement across the BBB (blood-brain barrier, also known as the brain endothelium) and into the CNS been identified. Based on increasing evidence about cryptococcal virulence factors, it is becoming apparent that a combination of virulence factors rather than a single one is most likely involved in the multistep process of cryptococcal dissemination and CNS invasion. See, e.g., Chalier, C. F., et al., (2005) Am J Path 166:421-432; Eigenheer, R. A., et al., (2007) FEMS Yeast Res 7:499-510; Jong, A., et al., (2007) Eukaryot Cell 6:1486-1496; Santangelo, R., et al., (2004) Infect. & Immun. 72:2229-2239; Steen, B. R., et al., (2003) Eukaryot Cell 2:1336-134; Olszewski, M A., et al., (2004) Am J of Path 164:1761-1771. However, our understanding of the process in which cryptococci transfer from the primary sites of infection to the CNS is incomplete.